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A brief review of the history of key observations of cingulate organization, particularly in the limbic system framework, is presented from 1907 to the present. The reasons why it has not played a significant role in neurology reflect the fact that its arterial supply is complex and no cingulate syndrome has been identified. A flat map of its eight subregions and areas is presented as a basis for many subsequent chapters in this volume. Along with this is a summary of current functional attributes of many of its divisions including cognitive, emotion, mental (Theory of Mind), skeletomotor, and autonomic output and various models of its function based on connectivity studies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mild traumatic brain injury (mTBI) is a condition of normal neuroimaging, because conventional MRI is not sensitive to brain lesions. Neurocognitive deficits persist for years after injury in 15% of patients. Persistent TAI can continue after the trauma and contribute to progressive disability. Neuropathologic studies underestimate the total axonal damage, by failure to identify fine-caliber unmyelinated fiber. Swollen axons represent the "tip of the iceberg" of damage. Progression of molecular changes, including mitochondrial dysfunction, leads to secondary injuries. Primary low-intensity "invisible injury" is solely detectable at ultrastructural levels. Over the long term, mTBI is not a static event but a progressive injury, increasing risk of neurodegenerative diseases. Lack of evidence of brain injury has led to the development of more sensitive methods: morphometric MRI (VBM, DTI) and functional techniques (fMRI, PET, SPECT). By deformation of the surface of gray matter cingulate gyrus and disruption of long-coursing WM of CB structures, striking the falx, mTBI causes alteration of cingulate functions. Postconcussion, blast, and whiplash-associated disorders are the main mechanisms providing behavior and cognitive symptoms after mTBI., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Once a diagnosis of Parkinson's disease (PD) has been made, even in its earliest prodromal form of subjective memory impairment, cognitive impairment has begun and involves anterior cingulate cortex (ACC). While the Braak staging scheme showed mid- to later-stage PD progression from cingulate allocortex adjacent to the corpus callosum and progressing into its neocortical moieties, the last decade has produced substantial information on the role of cingulate cortex in multiple symptoms, not just global measures of cognition. Voxel-based morphometry has been used in many studies of mild cognitive impairment (MCI) in PD to show reduced thickness in ACC and posterior cingulate cortex (PCC). Regional cerebral blood flow is altered in association with verbal IQ in all the PCC and anterior midcingulate cortex and executive impairments in ACC. Diffusion tensor imaging shows reduced fractional anisotropy throughout the entire cingulum bundle. Amnestic MCI is associated with reduced dopamine-2 receptor binding in ACC and, even in cognitively normal PD cases, dopaminergic pathways in ACC are impaired early in association with executive and language functions. The cholinergic system also has substantial changes in nicotinic and muscarinic receptor binding, and therapy with donepezil improves Mini-Mental State Exam scores and metabolism in pACC and dPCC. Cingulate cortex is also engaged in two critical symptoms: apathy and visual hallucinations. Finally, one can be optimistic that cingulate cortex will play an important role in developing new biomarkers of early PD. These methods have already been shown to be useful in cingulate cortex and include magnetic resonance spectroscopy, next-generation gene expression, and the new α-synuclein proximity ligation assay that specifically recognizes α-synuclein oligomers. Thus the future is bright for developing multivariate, multimodal biomarkers that include cingulate cortex., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Broca's (1878) definition of the limbic lobe referred to its being located at the edge of the cerebral cortex, and Papez (1937) and MacLean (1990) welded a series of medial surface structures into what we now know as the limbic system. The last four decades of research have provided a wealth of detailed information on the connectivity and functions of the limbic system and one can only conclude that it is not a uniform and single system. The cingulate cortex itself has three major divisions: anterior primarily for emotion, middle mainly for response selection and feedback-guided decision making, and posterior/retrosplenial cortices for visuospatial orientation and assessing the self-relevance of objects and events. Each of these divisions has a different cytoarchitecture and set of connections. The cingulate observations lead to a new framework of limbic organization: three limbic subsystems that include the amygdala, orbitofrontal cortex, the insula, the hippocampus, and, of course, the cingulate cortex. This concept is expanded in terms of connectivity among them and the underlying functions of each subsystem. The three limbic subsystems considered here are the "anterior emotional subsystem," the "middle sensorimotor subsystem," and the "posterior cognitive spatial map subsystem" for localizing personally relevant objects and episodes. A defining characteristic of the anterior emotional subsystem is its input from the amygdala. Another interesting outcome of this analysis is that the middle hippocampus and anterior midcingulate cortex share a role in approach-avoidance decision making suggesting a potential for connectional synergy. Thus, the concept of "a" limbic system needs radical revision to accommodate a minimum of three limbic subsystems. As this approach was initiated by the three-part composition of the cingulate cortex, a finer-grain analysis of the cingulate region shows that six limbic subsystems may be a more accurate reflection of limbic organization., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The entire cingulate cortex is engaged in the structure/function abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In ADHD, which is the most common developmental disease, impaired impulse control and cognition often trace to anterior midcingulate cortex (aMCC) in Go/No-go tests, decoding and reading, the Stroop Color and Word Test, and the Wisconsin Card Sorting Test (WCST), with volume deficits in anterior cingulate cortex (ACC) and posterior midcingulate cortex (pMCC). Volumes in pMCC correlate positively with the WCST and negatively with total and nonperseverative errors on the WCST. Activation and connectivity on N-back tests show connections for high and low spatial working memory, but patients have increased activation in PCC and decreased connectivity between MCC and PCC for high load. Students struggle in class due to malfunctioning aMCC, pregenual anterior cingulate cortex (pACC), and dorsal posterior cingulate cortex (dPCC), and to core deficits in response/task switching in aMCC. Gene mutations are found in the DA transporter and DA4 and DA5 receptors. Methylphenidate decreases hyperactivity in aMCC. The DA system is controlled by cholinergic receptors in the daMCC and genetics show nAChR mutations in alpha 3, 4, and 7 receptors. At 25 years, a modified Eriksen flanker/No-go task and voxel-based morphometry (VBM) show prenatal smoking, lifetime smoking at 13 years, and novelty seeking. Prenatal exposure to nicotine exhibits weaker responses in aMCC during cognitive tasks for hyperactivity/impulsiveness but not inattention. AZD1446 (ɑ4β2 nAChR agonist) improves the Groton Maze task due to high nAChR in dPCC/RSC engaged in spatial orientation. Environmental factors associated with childhood ADHD relate to pesticides, organochlorine, and air pollutants. Network connection segregation shows increased amygdala local nodal, but decreased ACC and PCC connections, reflecting emphasis on local periamygdala connections at the expense of cortical connections. Thus, ADHD children/adolescents respond impulsively to the significance of stimuli without having cortical inhibition. Finally, controls show negative relationships between aMCC and the default mode network, and ADHD compromises this relationship, showing decreased connectivity between ACC and precuneus/PCC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Conversion disorder is one of the terms used to describe various psychosomatic neurological symptoms that are thought to originate from a psychological conflict. Psychological stressors can usually be identified but appear to be almost similar to the severity of psychological stress in non-psychosomatic neurological disorders. Recent neuroimaging research provides one rather robust finding of increased activation in the anterior cingulate gyrus. This activation has been explained as a reflection of 'active inhibition' or 'self-monitoring' but its meaning in conversion disorder still remains mysterious. In this paper, current theories are re-examined from a neuroanatomical point of view.

Neuronal aggregates involved in conscious awareness are not evenly distributed throughout the CNS but comprise key components referred to as the neural network correlates of consciousness (NNCC). A critical node in this network is the posterior cingulate, precuneal, and retrosplenial cortices. The cytological and neurochemical composition of this region is reviewed in relation to the Brodmann map. This region has the highest level of cortical glucose metabolism and cytochrome c oxidase activity. Monkey studies suggest that the anterior thalamic projection likely drives retrosplenial and posterior cingulate cortex metabolism and that the midbrain projection to the anteroventral thalamic nucleus is a key coupling site between the brainstem system for arousal and cortical systems for cognitive processing and awareness. The pivotal role of the posterior cingulate, precuneal, and retrosplenial cortices in consciousness is demonstrated with posterior cingulate epilepsy cases, midcingulate lesions that de-afferent this region and are associated with unilateral sensory neglect, observations from stroke and vegetative state patients, alterations in blood flow during sleep, and the actions of general anesthetics. Since this region is critically involved in self reflection, it is not surprising that it is similarly a site for the NNCC. Interestingly, information processing during complex cognitive tasks and during aversive sensations such as pain induces efforts to terminate self reflection and result in decreased processing in posterior cingulate and precuneal cortices.

Cannabinoid receptors are found in moderate density throughout the cerebral cortex. The anterior cingulate cortex (ACC) is of particular interest due its high level of cannabinoid receptors and role in behaviors known to be modulated by cannabinoids. These studies were conducted to determine the cellular localization of cannabinoid receptors and to compare the level of cannabinoid receptor binding with receptor-mediated G-protein activity in the rat ACC. Either ibotenic acid or undercut lesions were made in ACC, and brains were processed for [3H]WIN 55,212-2 and WIN 55,212-2-stimulated [35S]GTPgammaS autoradiography. Both cannabinoid receptors and receptor-activated G-proteins were highest in laminae I and VI of ACC in control tissue. Although similar levels of receptor binding were found in these laminae, significantly higher levels of receptor-activated G-proteins were found in lamina VI. Ibotenic acid lesions that destroyed ACC neurons decreased [3H]WIN 55,212-2 binding by 60-70% and eliminated WIN 55,212-2-stimulated [35S]GTPgammaS binding. In contrast, deafferentation of the ACC with undercut lesions had no significant effect on cannabinoid receptor binding or G-protein activation. These results indicate that cannabinoid receptors in laminae I and VI of the ACC are located on somatodendritic elements or axons intrinsic to the ACC. In addition, differences in the relative levels of cannabinoid binding sites and activated G-proteins between cortical laminae indicate that the efficiency of cannabinoid receptors for G-protein activation may vary within a specific brain region.